A transplant is a complex medical treatment that allows the replacement of diseased organs in an individual, improving his quality of life or even allowing his survival.
Transplant rejection is one of the greatest challenges to transplantation. It is the outcome of the natural response of the immune system to a foreign substance, or antigen. This complex process is mainly T-lymphocyte mediated, although it involves serial interactions between foreign antigens, antibodies, T lymphocytes, macrophages, cytokines (also known as lymphokines or interleukins), adhesion molecules (ie, co-stimulatory molecules), and membrane proteins that enhance binding of T lymphocytes and B lymphocytes.
The goal of immunosuppressive therapy is to prevent and treat transplant rejection as well as to prolong transplant and patient survival. However, due to the potency of immunosupressive agents and inter- and intra-individual variability in pharmacokinetics, dose individualization is required to maintain adequate immunosuppression while minimizing adverse reactions. Poor water solubility and bioavailability contribute to the complexity of dosing immunosuppressive agents such as cyclosporine and sirolimus.
Transplant rejection can be hyperacute (within the first hours after transplantation or during the early days) caused by preformed antibodies, acute (during the early days or months) caused by T-lymphocytes or chronic (months or even years later) mainly caused antibodies. The development of methodologies to predict and/or prevent rejection would increase transplant success.
Due to a worldwide shortage of available human organs for transplantation, xenotransplantation (transplantation of living cells, tissues or organs from one species to another) is a valuable alternative to conventional allotransplantation (same-species transplant). Nonhuman primates were first considered as a potential organ source for xenotransplantation to humans. Chimpanzees were originally considered to be the best option, since their organs are of similar size and they have good blood type compatibility with humans. However, since chimpanzees are listed as an endangered species, other potential donors were sought out. Baboons are more readily available, however they are also not practical as potential donors. Problems include their smaller body size, the infrequency of blood group O (the universal donor), their long gestation period, and that they typically produce few offspring. In addition, a major problem with the use of nonhuman primates is the increased risk of disease transmission, since they are so closely related to humans. Pigs are currently thought to be the best candidates for organ donation. The risk of cross-species disease transmission is decreased because of their increased phylogenetic distance from humans. They are readily available, their organs are anatomically comparable in size, and new infectious agents are less likely since they have been in close contact with humans through domestication for many generations.
In order to overcome hyperacute rejection after xenotransplantation, animal organ/tissues have been engineered for their use in xenotransplantation. An alternative strategy to avoid rejection of xenogeneic cells is disclosed in EP 0661980, which involves removal of xenoantibodies from the blood of the recipient and/or inhibition of xenoantibodies in vivo.
Different markers with a predictive value of transplant rejection have been described in the art. WO2011/119980 discloses methods for determining whether a subject who has received an allograft is undergoing acute rejection that comprise evaluating the level of a plurality of biomarkers, including CD44, EMOD, PEDF in a sample from a subject who has received the allotranplant. US2003175811A1 discloses the use of proteins, such as MLC2, TPM1, troponine C or actin, or antibodies against them as markers for the diagnosis and/or prognosis of acute rejection. Johnson L B et al. shows that serum hyaluronic acid (HA) can detect endothelial cell dysfunction following liver transplantation in patients with rejection, primary non-function or vascular thrombosis, indicating that serum HA may provide a noninvasive measure for early graft function (Johnson L B et al. 2008 American Journal of Transplantation 3 (Suppl 5): 378). Fábrega E et al. shows that the release of circulating adhesion molecules is a prominent feature coinciding with the first episode of hepatic rejection, and that hyaluronan levels may be a sensitive marker of liver endothelial cell function in the postoperative period of liver transplantation (Fábrega E et al. 2000 Transplantation 69:569-573).
Thus, there is a need in the state of the art to identify reliable alternative markers and/or predictors for allotransplant and/or xenotransplant rejection in order to overcome the problems associated to transplant rejection and to improve the overall survival of patients undergoing transplantation.